The role of aryl hydrocarbon receptor in the occurrence and development of periodontitis

Abstract

Periodontitis is a condition characterized by dysbiosis of microbiota and compromised host immunological responses, resulting in the degradation of periodontal tissues. The aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, plays a crucial role in the pathogenesis of periodontitis. AHR serves as a pivotal mediator for the adverse impacts of exogenous pollutants on oral health. Research indicates elevated expression of AHR in individuals with periodontitis compared to those without the condition. However, subsequent to the identification of endogenous AHR ligands, researches have elucidated numerous significant advantageous roles associated with AHR activation in bone, immune, and epithelial cells. This review concentrates on the modulation of the AHR pathway and the intricate functions that AHR plays in periodontitis. It discusses the characteristics of AHR ligands, detailing the established physiological functions in maintaining alveolar bone equilibrium, regulating immunity, facilitating interactions between the oral microbiome and host, and providing protection to epithelial tissues, while also exploring its potential roles in systemic disorders related to periodontitis.

Keywords: AHR; alveolar bone homeostasis; oral microbiome-host interactions; periodontitis; tryptophan metabolism.

Figure 1

Mechanisms of AHR signaling. In its basal state, AHR associates with HSP90, p23, XAP2 (ARA9/AIP), and SRC to maintain its cytoplasmic localization. Upon ligand binding, AHR undergoes a conformational alteration and translocates into the nucleus. It dissociates from this complex and subsequently forms a heterodimer with the AHR nuclear translocation protein (ARNT). This AHR-ARNT heterodimer translocates to the nucleus, where it regulates the expression of downstream target genes by binding to xenobiotic response elements (XREs). Target genes include cytochrome P450 family 1 subfamily A member 1 (CYP1A1), CYP1B1, and AHR repressor (AHRR), among others involved in various signaling pathways. The AHRR, in turn, modulates AHR activity through a negative feedback mechanism. Created in BioRender. qwe, s. (2024) BioRender.com/z56o095.

Figure 2

Summary of the sources of AHR ligands. AHR ligands fall into two categories: endogenous and exogenous. Exogenous ligands include synthetic aromatic hydrocarbons from pollutants and carcinogens, as well as natural compounds from vegetables and fruits. Endogenous ligands mainly come from tryptophan metabolism by the host and microbiota. Within the host, Trp is predominantly metabolized through the kynurenine (KYN) metabolic pathway. Trp is enzymatically converted by either indolamine-2, 3-dioxygenase (IDO) or tryptophan-2, 3-dioxygenase (TDO) to Kynurenine. Kynurenine undergoes conversion to kynurenic acid via the enzymatic activity of kynurenine aminotransferase (KAT), and to 3-hydroxykynurenine through the action of kynurenine 3-monooxygenase (KMO). Subsequently, it is metabolized into various products, including kynurenic acid, kynurenine, and quinolinic acid. 6-formylindolo[3,2-b]carbazole (FICZ) is produced as a result of the light or ROS in the skin. Another important source of ligand for AHR are microbial metabolites of tryptophan. Bacteria metabolize tryptophan into indole via the tnaA enzyme and can further metabolize it into indole-3-pyruvic acid (IPYA), indole-3-lactic acid (ILA), indole-3-acetaldehyde (IA), and indole-3-propionic acid (IPA). Additionally, they can convert tryptophan into tryptamine, indole-3-acetaldehyde (IAald), and tryptophol, or into indole-3-acetic acid (IAA) and indole-3-acetaldehyde (IAld).

Figure 3

The role of AHR in the periodontal tissue. Upon activation by exogenous or endogenous ligands, the Aryl Hydrocarbon Receptor (AHR) exerts a multitude of functions within periodontal tissue. AHR demonstrates intricate regulatory mechanisms in maintaining bone homeostasis by modulating the biological processes of osteoblasts, osteoclasts, and periodontal ligament cells (PDLCs). Activation of AHR can influence inflammation and immune responses in periodontal tissue by affecting the equilibrium between effector T cells and regulatory T cells (Tregs), macrophage polarization, dendritic cell (DC) differentiation, and the production of various inflammatory mediators. AHR activation in the host also has the potential to promote a state of equilibrium between the host and microbial communities and exert a protective effect on the gingival epithelial barrier. Created in BioRender. Feng, B. (2024) BioRender.com/v13j704.

Figure 4

AHR in the relationship between periodontitis and systemic diseases. AHR links periodontitis to systemic diseases like Alzheimer’s, rheumatoid arthritis (RA) and diabetes. Periodontitis may increase Alzheimer’s risk by disrupting brain vascular homeostasis and the blood-brain barrier through AHR signaling. Pathogens from periodontitis affect immune balance, potentially accelerating RA progression via abnormal AHR activation. Synthetic aromatic hydrocarbons represent a common risk factor for both periodontitis and diabetes. Created in BioRender. Feng, B. (2024) BioRender.com/v59o971.